Deuterated 3-piperidinopropiophenone and medicaments containing said compounds

ABSTRACT

The invention discloses deuterated 3-piperidinopropiophenones as well as their physiologically tolerated salts. Furthermore, the invention concerns the use of deuterated 3-piperidinopropiophenones for the treatment of muscular illnesses as well as for the preparation of pharmaceutical drugs for the treatment of muscular illnesses. 
     In addition, the invention discloses pharmaceutical formulations containing deuterated 3-piperidinopropiophenones as well as their physiologically tolerated salts for the treatment of muscular illnesses in addition to containing pharmaceutically tolerated adjuvants and/or additives.

The invention concerns deuterated 3-piperidinopropiophenones and theirphysiologically tolerated salts as well as pharmaceutical drugscontaining these compounds.

Known representatives of 3-piperidinopropiophenones are tolperisone andeperisone (U.S. Pat. No. 3,995,047, U.S. Pat. No. 4,638,009). Thesecompounds are used as spasmolytics and vasodilators.

The problem of the present invention is to make available3-piperidinopropiophenones that, in comparison to the already knowncompounds, have improved pharmacokinetic and/or pharmacodynamicproperties.

Surprisingly, it has now been found that the deuterated3-piperidinopropiophenones in accordance with the invention haveappreciably better pharmacokinetic and/or pharmacodynamic propertiesthan the undeuterated compounds.

Thus, in accordance with the invention, the problem is solved by makingavailable deuterated 3-piperidinopropiophenones of the general formulaI,

whereinR represents an undeuterated, a mono- or polydeuterated, or aperdeuterated alkyl group containing up to 3 C atoms, the groups R′ areall hydrogen or, in common, all represent deuterium, the groups R″ are,independently of one another, deuterium or hydrogen, and wherein atleast one of the groups R, R′, or R″ is deuterium or contains deuterium,as well as their physiologically tolerated salts.

Preferred are the following deuterated 3-piperidinopropiophenones inaccordance with the invention:

4′-deuteromethyl-2-methyl-3-piperidinopropiophenone,

4′-methyl-2′,3′,5′,6′-tetradeutero-2-methyl-3-piperidinopropiophenone,

4′-ethyl-2′,3′,5′,6′-tetradeutero-2-methyl-3-piperidinopropiophenone,

4′-isopropyl-2′,3′,5′,6′-tetradeutero-2-methyl-3-piperidinopropiophenone,

4′-n-propyl-2′,3′,5′,6′-tetradeutero-2-methyl-3-piperidinopropiophenone,

4′-trideuteromethyl-2′,3′,5′,6′-tetradeutero-2-methyl-3-piperidinopropiophenone,

4′-methyl-2-deuteromethyl-2-deuterium-3-piperidinopropiophenone,

4′-methyl-2-deuteromethyl-2-deuterium-3,3-dideutero-3-piperidinopropiophenone, and

4′-trideuteromethyl-2′,3′,5′,6′-tetradeutero-2-methyl-3,3-dideutero-3-piperidinopropiophenone.

Preferred is the use of the deuterated 3-piperidinopropiophenones inaccordance with the invention as well as their physiologically toleratedsalts for the treatment of illnesses with symptoms in the muscularregion.

Especially preferred is the use of deuterated 3-piperidinopropiophenonesas well as their physiologically tolerated salts for the preparation ofpharmaceutical drugs for the treatment of illnesses with symptoms in themuscular region.

Especially preferred are pharmaceutical formulations that contain thedeuterated 3-piperidinopropiophenones in accordance with the inventionas well as their physiologically tolerated salts for the treatment ofillnesses with symptoms in the muscular region in addition to containingpharmaceutically tolerated adjuvants and/or additives.

The preparation of the deuterated tolperisone that is used in accordancewith the invention is in itself known. The deuterated propiophenonesemployed as starting compound were prepared using deuterated toluenederivatives by Friedel-Crafts acylation with propionyl chloride(Organikum, 15th edition, 1977, pp. 404-405). Used in this process werethe commercially obtainable toluene derivatives trideuteromethylbenzeneand perdeuterotoluene and the known 2,3,4,5,6-pentadeuterotoluene (A.Borovik et al., Angew. Chem., Int. Ed., 2000, 39(22), 4117-4118).

The reaction to give the deuterated tolperisone derivatives can takeplace in analogy to the known syntheses for 3H-tolperisone (Dietrich,A.; Fels, G.; J. Labelled Compd. Radiopharm. (1999), 42(12), 1125-1134,as well as Dietrich, A.; Dissertation 1999, Univ.-GH Paderborn).

In this work, A. Dietrich describes, among other things, the synthesisof tolperisone derivatives that are tritiated and deuterated in the 3′position and in the 3′,5′ position. These substances were used for theinvestigation of the mode of action and pharmacology of tolperisone.

The tolperisone derivatives that are deuterated in the 2 position and inthe 2-methyl position were produced, starting from the known2,3-didehydrotolperisone (Dietrich, A., Dissertation 1999, Univ.-GHPaderborn), by reaction with deuterium. The compounds that aredeuterated in the 1 position were obtained in a way that is in itselfknown by the use of deuterated paraformaldehyde in the Mannich reactionwith the corresponding propiophenone derivatives.

Conventional physiologically tolerated inorganic and organic acids are,for example, hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid,tartaric acid, malic acid, citric acid, salicylic acid, adipic acid, andbenzoic acid. Further salts that can be used are described, for example,in Fortschritte der Arzneimittelforschung [Progress in Drug Research],Vol. 10, pages 224-225, Birkhäuser Publishers, Basel and Stuttgart,1966, and Journal of Pharmaceutical Sciences, Vol. 66, pages 1-5 (1977).

The acid addition salts are obtained, as a rule, in a way that is initself known by mixing the free base or solutions thereof with thecorresponding acid or solutions thereof in an organic solvent, such as,for example, in a lower alcohol, such as methanol, ethanol, n-propanol,or isopropanol, or in a lower ketone, such as acetone, methyl ethylketone, or methyl isobutyl ketone, or in an ether, such as diethylether, tetrahydrofuran, or dioxane. In order to achieve betterseparation of the crystals, it is also possible to use mixtures of thesolvents mentioned. Beyond this, it is possible to preparephysiologically tolerated aqueous solutions of acid addition salts ofthe compounds used in accordance with the invention in an aqueous acidsolution.

The acid addition salts of the compounds in accordance with theinvention can be transformed into the free base in ways that are inthemselves known—for example, with alkalis or ion exchangers. Additionalsalts can be obtained from the free base by reaction with inorganic ororganic acids, in particular with those suitable for the formation ofsalts that can be used therapeutically. These or else other salts of thenew compound, such as, for example, the picrate, can also serve for thepurification of the free base by transforming the free base into a salt,separating the latter, and liberating the base once again from the salt.

The subject of the present invention is also pharmaceutical drugs fororal, rectal, topical (cutaneous, transdermal, local), subcutaneous,intravenous, or intramuscular application that, in addition toconventional carriers and diluents, contain a compound of the generalformula I or its acid addition salt as the active ingredient.

The pharmaceutical drugs of the invention are prepared in a known way ina suitable dosage with the conventional solid or liquid carriers ordiluents and the conventionally used technical pharmaceutical adjuvantsdepending on the desired kind of application. The preferred formulationsconsist of a form of administration that is suitable for oralapplication. Such forms of administration are, for example, tablets,film tablets, dragées, capsules, pills, powders, solutions, orsuspensions or depot forms.

The topical application can take place, for example, in the form ofsalves, creams, gels, solutions, or bandages.

Obviously, parenteral formulations, such as injection solutions, alsocome into consideration. Furthermore, suppositories are also mentionedas formulations by way of example.

Corresponding tablets can, for example, be obtained by mixing the activeingredient with known adjuvants, such as, for example, inert diluents,such as dextrose, sugar, sorbitol, mannitol, polyvinyl pyrrolidone,disintegrators, such as cornstarch or alginic acid, binders, such asstarches or gelatins, lubricants, such as magnesium stearate or talc,and/or means for achieving a depot effect, such ascarboxylpolymethylene, carboxylmethylcellulose, cellulose acetatephthalate, or polyvinyl acetate. The tablets can also consist of severallayers.

In a corresponding manner, dragées can be prepared by coating cores,prepared in analogy to the tablets, with substances usually used indragée coats, such as, for example, polyvinyl pyrrolidone or shellac,gum arabic, talc, titanium dioxide, or sugar. Here, the dragée shell canalso consist of several layers, wherein the adjuvants mentioned abovefor the tablets can be used.

Solutions or suspensions containing the active ingredient used inaccordance with the invention can contain, in addition, substances thatimprove taste, such as saccharin, cyclamate, or sugar, as well as, forexample, flavoring substances, such as vanilla or orange extract. Inaddition, they can contain suspending agents, such as sodiumcarboxymethylcellulose, or preservatives, such as p-hydroxybenzoates.For example, capsules that contain active ingredients can be prepared bymixing the active ingredient with an inert carrier, such as lactose orsorbitol, followed by encapsulation in gelatin capsules.

Suitable suppositories can be prepared, for example, by admixture withcarriers, such as neutral fats or polyethylene glycol or theirderivatives, which are provided for this purpose.

The preparation of the pharmaceutical drug in accordance with theinvention for topical application is known to the person skilled in theart. In the preparation of the pharmaceutical drug in accordance withthe invention for transdermal application, the adjuvants and enhancersthat are in themselves known are used.

The preparation of the pharmaceutical formulations in accordance withthe invention is in itself known and is described in handbooks known tothe person skilled in the art, such as, for example Hager's Handbuch[Hager's Handbook] (5th) 2, 622-1045; List et al., Arzneiformenlehre[Drug Forms], Stuttgart: Wiss. Pub. Co. 1985; Sucker et al.,Pharmazeutische Technologie [Pharmaceutical Technology], Stuttgart:Thieme 1991; Ullmann's Enzyklopädie [Ullmann's Encyclopedia] (5th) A 19,241-271; Voigt, Pharmazeutische Technologie [Pharmaceutical Technology],Berlin: Ullstein Mosby 1995.

The pharmaceutical drugs prepared in this way can be used for thetreatment of illnesses with symptoms in the muscular region.

The compounds in accordance with the invention have a number ofadvantages in comparison with the compounds known in the prior art,which do not bear any deuterium. The deuteration brings about a changein metabolism in the organism. In particular, the hydroxylation on thephenyl group is impeded, this leading to a reduced first-pass effect. Inthis way it is possible to change the dosage and to create longer-actingformulations, which, in the form of depot formulations, can also improvecompliance.

In addition, the pharmacodynamics are also changed, because thedeuterated compounds form completely different hydrate shells, so thatthe distribution in the organism differs markedly from that of theundeuterated compounds.

The metabolism of tolperisone and of substances derived therefrom occursprimarily in the liver, this resulting in the observation of a strongfirst-pass effect. Only one-fifth of the administered dose is once againfound unchanged in the blood.

Decisive for the hepatic metabolism of medications and xenobiotics arecytochrome P450 (CYP) enzymes. The primary metabolites during hepaticdegradation are formed by hydroxylation of the alkyl substituentslocated on the aromatic ring and by hydroxylation of the aromatic ringsthemselves (Miyazaki, Ishibashi Takayama; 4th symposium on DrugMetabolism and Action, 1972, Sendai; Japan: 154-164).

In order to obtain more detailed knowledge regarding the hepaticmetabolism of tolperisone and of the claimed deuterated analogs,pharmacokinetic in-vitro studies were carried out with the cytochromeP450 families (CYP1A1, CYP1A2, CYP2C8, CYP2C19, CYP2D6, CYP2E1, CYP3A4)that are known to the person of average skill in the art and are mostcommonly encountered in the liver.

The results of these investigations are presented in FIGS. 1 to 3.

Shown therein are the following:

FIG. 1 shows the enzymatic degradation of tolperisone by cytochromeoxidases;

FIG. 2 shows the formation of hydroxy metabolites from tolperisone byCYP2D6 and CYP2C19 in comparison to less active cytochromes; and

FIG. 3 shows the formation of hydroxy metabolites from compound I bycytochrome P450 enzymes.

FIG. 1 shows the different decreases in tolperisone concentration due toenzymatic degradation by cytochrome oxidases over time.

In accordance therewith, tolperisone is transformed above all by CYP2C19and CYP2D6. The other cytochromes investigated contribute at mostinsignificantly to the biological degradation of tolperisone.

The primary metabolites that are formed by hydroxylation are formed byCYP2C19 and CYP2D6 to the same extent as the substrate is degraded (seeFIG. 2).

Surprisingly, the hepatic metabolism of the deuterated compounds inaccordance with the invention by cytochrome P450 oxidases differsmarkedly from that of the corresponding undeuterated substances.

For example, the enzymatic hydroxylation of1-[4-(trideuteromethyl)tetradeuterophenyl]-2-methyl-3-piperidin-1-yl-1-propanone(I; formula I with R=CD₃, R′=D, R″=H) by CYP2C19 and CYP2D6 iseffectively retarded by a factor of 10 in comparison to that oftolperisone (see FIG. 3).

This results in an improvement in the effectiveness, because it iscompelling to assume a prolongation in the duration of action. Thetherapeutic benefit lies in a reduction in dose when pharmaceuticaldrugs prepared from the deuterated propiophenones in accordance with theinvention are used in comparison to the previously used non-deuteratedanalogous compounds.

Accordingly, it is possible to develop completely novel formulationforms.

The following examples illustrate the invention:

EXAMPLE 1

Preparation of 4′-trideuteromethylpropiophenone

In a three-neck flask equipped with a stirrer, a dropping funnel, and areflux condenser with a calcium chloride drying tube, 40 mL ofdichloroethane were treated with 16 mg of anhydrous, finely powderedaluminum chloride. Under ice cooling, 13.88 g of propionyl chloride wereadded dropwise. Then, 9.5 g of trideuteromethylbenzene (toluene-d3) wereadded dropwise at such a rate that the temperature of the reactionsolution was kept constant at 20° C. After the addition had ended, themixture was stirred for 2 hours and subsequently allowed to standovernight. The ketone-aluminum chloride complex that formed wasdecomposed by pouring the reaction mixture carefully onto 50 mL of ice.The organic phase was separated off and the aqueous phase was extractedthree times with dichloroethane. The combined organic extracts werewashed with water, 2% aqueous sodium hydroxide solution, and once againwith water and then dried over potassium carbonate.

The solvent was removed and the residue was distilled in vacuum. Yield:10.2 g (68%) of 4′-trideuteromethypropiophenone as a colorless liquid.

C₁₀H₉D₃O: 151.223

Calcd. C 79.43 H 9.99

Found C 79.41 H 10.01

¹H-NMR: In comparison to the ¹H-NMR spectrum of the non-deuterated4′-methylpropiophenone, it was possible to establish the absence of theresonance signal of the aromatic CH₃ group in the ¹H-NMR spectrum of theproduct, the spectra being otherwise in agreement.

EXAMPLE 2

Preparation of 4′-trideuteromethyl-2′,3′,5′,6′-tetradeuteropropiophenoneIn analogy to Example 1, 16 g of anhydrous, finely powdered aluminumchloride in 40 mL of dichloroethane were treated under ice cooling with13.88 g of propionyl chloride and brought to reaction with 10.02 g oftrideuteromethyl-2,3,4,5,6-tetradeuterobenzene [toluene-d8].

In this case, however, the ketone-aluminum chloride complex wasdecomposed by pouring the reaction mixture into ice-cooled D₂O. Thefurther workup was conducted in analogy to Example 1.

Yield: 10.24 g (66%) of4′-trideuteromethyl-2′,3′,5′,6′-tetradeuterophenylpropiophenone* as acolorless liquid. *Presumably,“4′-trideuteromethyl-2′,3′,5′,6′-tetradeuteropropiophenone” ismeant.—Translator's Note.

C₁₀H₅D₇O:

Calcd. C 77.37 H 12.33

Found C 77.40 H 12.31

¹H-NMR: In comparison to the ¹H-NMR spectrum of the non-deuterated4′-methylpropiophenone, it was possible to establish the absence of theresonance signal of the aromatic CH₃ group as well of the aromaticprotons in the ¹H-NMR spectrum of the product, the spectra beingotherwise in agreement.

EXAMPLE 3

Preparation of 4′-methyl-2′,3′,5′,6′-tetradeuteropropiophenone Inanalogy to Example 2, 16 g of anhydrous, finely powdered aluminumchloride in 40 mL of dichloroethane were treated under ice cooling with13.88 g of propionyl chloride and brought to reaction with 9.72 g of2,3,4,5,6-pentadeuterotoluene [toluene-d5]. The workup took place asdescribed in Example 1.

Yield: 9.59 g (63%) of 4′-methyl-2′,3′,5′,6′-tetradeuteropropiophenoneas a colorless liquid.

C₁₀H₈D₄O:

Calcd. C 78.9 H 10.59

Found C 79.3 H 10.53

¹H-NMR: In comparison to the ¹H-NMR spectrum of the non-deuterated4′-methylpropiophenone, it was possible to establish the absence of theresonance signal of the aromatic protons in the ¹H-NMR spectrum of theproduct, the spectra being otherwise in agreement.

EXAMPLE 4

Preparation of 4′-trideuteromethyl-2-methyl-3-piperidinopropiophenone1.15 g of 4′-trideuteromethylpropiophenone were dissolved in 5 mL ofmethanol and subsequently 0.3 g of paraformaldehyde and 1.1 g ofpiperidine hydrochloride were added under stirring. The reaction mixturewas heated to reflux until the end point of the reaction was reached(solidification of the reaction mixture). Subsequently, 10 mL ofchloroform were added, the organic phases were dried over sodium sulfateand filtered, and the solvent was removed in vacuum. The obtained solidwas finely pulverized and washed with acetone. The 1.5 g of thecrystalline crude product obtained was converted into the hydrochloride,which was recrystallized from methanol.

Yield: 1.45 g (73%) in the form of needles.

Melting point: 167-169° C.

¹H-NMR (200 MHz, CDCl₃): δ=1.18 (d, 3H, CH₃), 1.25-1.68 (m, 6H, 3×CH₂),2.18-2.45 (m, 4H, 2×CH₂), 2.35 and 2.65 (d and AB spectrum, J=7.1 Hz,J_(A,B)=12.4 Hz, 2H, CH₂), 3.69 (m, 1H, CH), 7.78 (s, 4H, Ar—H).

¹³C-NMR (50 MHz, CDCl₃): δ=18.00 (Ar—CD₃), 20.01 (CH₃), 22.15 (CH₂),23.15 (CH₂), 34.25 (CH), 52.67 (2 CH₂), 58.53 (CH₂), 126.73 (C_(arom)),129.42 (C_(arom)), 131.34 (C_(arom)), 155.02 (C_(arom)), 204.02 (C:O).

C₁₆H₂₀NOD₃ · HCl (284.85):

Calcd. C 67.47 H 9.55 N 4.92

Found C 67.45 H 9.56 N 4.91

EXAMPLE 5

Preparation of4′-methyl-2′,3′,5′,6′-tetradeutero-2-methyl-3-piperidinopropiophenone

In analogy to Example 4, 1.16 g of4′-methyl-2′,3′,5′,6′-tetradeuteropropiophenone were dissolved in 5 mLof methanol and subsequently brought to reaction with 0.3 g ofparaformaldehyde and 1.1 g of piperidine hydrochloride. The product wasisolated as the hydrochloride.

Yield: 1.42 g (71%) in the form of needles.

Melting point: 174-176° C.

¹H-NMR (200 MHz, CDCl₃): δ=1.18 (d, 3H, CH₃), 1.25-1.68 (m, 6H, 3 CH₂),2.18-2.45 (m, 4H, 2 CH₂), 2.35 and 2.65 (d and AB spectrum, J=7.1 Hz,J_(A,B)=12.4 Hz, 2H, CH₂), 2.41 (s, 3H, Ar—CH₃), 3.69 (m, 1H, CH).

C₁₆H₁₉NOD₄ HCl (285.85)

Calcd. C 67.23 H 9.87 N 4.9

Found C 67.21 H 9.89 N 4.8

EXAMPLE 6

Preparation of4′-trideuteromethyl-2′,3′,5′,6′-tetradeutero-2-methyl-3-piperidinopropiophenone

In analogy to Example 4, 1.09 g of4′-trideuteromethyl-2′,3′,5′,6′-tetradeuteropropiophenone were dissolvedin 5 mL of methanol and subsequently brought to reaction with 0.3 g ofparaformaldehyde and 1.1 g of piperidine hydrochloride. The product wasisolated as the hydrochloride.

Yield: 1.46 g (72%) in the form of needles. Melting point: 177-178° C.

C₁₆H₁₆NOD₇ · HCl (288.87)

Calcd. C 66.53 H 10.81 N 4.85

Found C 66.55 H 10.84 N 4.87

¹H-NMR (200 MHz, CDCl₃): δ=1.18 (d, 3H, CH₃), 1.25-1.68 (m, 6H, 3 CH₂),2.18-2.45 (m, 4H, 2 CH₂), 2.35 and 2.65 (d and AB spectrum, J=7.1 Hz,J_(A,B)=12.4 Hz, 2H, CH₂), 3.69 (m, 1H, CH).

IR: ν_(max) (Nujol) 2721, 2639, 2532, 2408, 1674 (C:O), 1580 (Ar), 1544,1460, 1411, 1378, 1331, 1298, 1244, 1211, 1159, 1121, 1083, 1081, 1021,721, 638 cm⁻¹.

EXAMPLE 7

Preparation of4′-methyl-2-deuteromethyl-2-deuterium-3-piperidinopropiophenone

To a solution of 10 g (41 mmol) of 2,3-didehydrotolperisone in 150 mL ofethyl acetate were added 100 mg of Pd/C (10%) and the reaction flask wasflushed with deuterium gas and then joined to a Paar apparatus. Thedeuteration takes place at 2 atm at room temperature overnight. Thereaction mixture was filtered off over Celite and the filtrate wasconcentrated in vacuum. Subsequently, the residue was taken up in 1NNaOH and extracted with diethyl ether and the organic phase wasseparated off, dried over sodium sulfate, filtered, and concentrated invacuum. The resulting amine was dissolved in diethyl ether and acetylchloride and methanol were added in order to prepare the hydrochloride.

Yield: 8.6 g (85%) of the deuterated tolperisone were obtained.

Melting point: 178° C.

¹H-NMR (200 MHz, CDCl₃): δ=1.15 (d, 2H, CDH₂), 1.30-1.72 (m, 6H, 3 CH₂),2.20-2.48 (m, 4H, 2 CH₂), 2.48 (s, 3H, CH₃), 2.49 and 2.85 (d and ABspectrum, J=7.2 Hz, J_(A,B)=12.6 Hz, 2H, CH₂), 7.95 (s, 2H, AR—H).

¹³C-NMR (50 MHz, CDCl₃): δ=19.21 (Ar—CH₃), 18.78 (CDH₂), 22.20 (CH₂),22.95 (CH₂), 35.32 (CD), 52.53 (2 CH₂), 58.60 (CH₂), 129.33 (C_(arom)),130.32 (C_(arom)), 132.15 (C_(arom)), 145.55 (s, C_(arom)), 201.02(C:O).

C₁₆H₂₁NOD₂ HCl (283.48):

Calcd. C 67.71 H 9.23 N 4.93

Found C 67.73 H 9.21 N 4.95

EXAMPLE 8

In-vitro experiments on biological degradation of test substances bycytochrome P450 enzymes

Cell lines used: CYP1A1, CYP1A2, CYP2C8, CYP2C19, CYP2D6, CYP2E1,CYP3A4.

Incubation at 37° C. in 200 μL of incubation solution consisting of 0.1Mpotassium phosphate or 0.5M Tris HCl buffer (pH 7.4), 3 mM NADPH with aprotein concentration of 0.5 mg/mL.

The analysis of the enzyme test was conducted by means of LC/MS/MS.

1. A deuterated 3-piperidinopropiophenone of the general formula I,

wherein R represents an undeuterated, a mono- or polydeuterated, or aperdeuterated alkyl group containing up to 3 C atoms, the groups R′ areall hydrogen or all represent deuterium, the groups R″ are,independently of one another, deuterium or hydrogen, and wherein atleast one of the groups R, R′, or R″ is deuterium or contains deuterium,as well as their physiologically tolerated salts.
 2. The deuterated3-piperidinooropiophenone according to claim 1, namely,4′-trideuteromethyl-2-methyl-3-piperidinopropiophenone, 4′-methyl-2′,3′, 5′, 6′-tetradeutero-2-methyl-3-piperidinopropiophenone, 4′-ethyl-2′,3′, 5′, 6′-tetradeutero-2-methyl-3-piperidinopropiophenone,4′-isopropyl-2′, 3′, 5′,6′-tetradeutero-2-methyl-3-piperidinopropiophenone, 4′-n-propyl-2′, 3′,5′, 6′-tetradeutero-2-methyl-3-piperidinopropiophenone,4′-trideuteromethyl-2′, 3′, 5′,6′-tetradeutero-2-methyl-3-piperidinopropiophenone,4′-methyl-2-deuteromethyl-2-deuterium -3-piperidinopropiophenone,4′-methyl-2-deuteromethyl-2-deuterium-3,3-dideutero-3-piperidinopropiophenone,and 4′-trideuteromethyl-2′, 3′, 5′,6-tetradeutero-2-methyl-3,3-dideutero-3-piperidino-propiophenone.
 3. Amethod of treating a patient in need of at least one of a spasmolyticand a vasodilator comprising administering to the patient an effectiveamount of the deuterated 3-piperidinopropiophenone according to claim 1or 2 or its physiologically tolerated salts.
 4. A method of making apharmaceutical drug, said method comprising the steps of providing thedeuterated 3-piperidinopropiophenone according to claim 1 or 2 or itsphysiologically tolerated salts and mixing said deuterated3-piperidinopropiophenone or its physiologically tolerated salts with asuitable vehicle.
 5. Pharmaceutical formulation containing thedeuterated 3-piperidinopropiophenone according to claim 1 or 2 or itsphysiologically tolerated salts in addition to pharmaceuticallytolerated adjuvants and/or additives.
 6. The deuterated3-piperidinopropiophenone according to claim 1 or 2 in substantiallyisolated form.